There may be no link between serotonin levels and depression, according to an analysis of 17 studies. This raises questions about antidepressants that focus on this brain-signalling molecule, say the authors of the analysis. Not everyone is convinced by the findings, though.
The serotonin hypothesis, which dates from the 1960s, says that a chemical imbalance in the brain, including low levels of serotonin, also known as 5-hydroxytryptamine or 5-HT, leads to depression. We now think various biological, psychological and environmental factors play a role, but the most popular antidepressants, known as selective serotonin reuptake inhibitors (SSRIs), increase the availability of serotonin in the brain.
Now, Joanna Moncrieff at University College London and her colleagues have done an “umbrella analysis” of 17 systematic reviews and studies, which together included hundreds of thousands of people with and without depression.
It is difficult to directly measure real-time serotonin levels in the brain, so the 17 studies looked at depression and proxies for serotonin, such as the molecules in cerebral fluid that serotonin breaks down into; the levels of serotonin receptors and how active they are; or whether there are more genes for serotonin transporters – which remove serotonin – in people with depression.
Moncrieff’s team found that there was no evidence that low serotonin activity or amounts cause depression.
“The implication of our paper is that we do not know what [SSRI] antidepressants are doing,” says Moncrieff. One possibility is that they are working through a placebo effect, she says.
However, Johan Lundberg at the Karolinska Institute in Sweden says a limitation of the analysis is that it didn’t distinguish between people who had ongoing depression and those who have episodes of depression, whose state at the time they were assessed could affect the functioning of their serotonin systems. “It is key to separately analyse data from studies that examine the same patients when ill and when in remission, to have optimal conditions to examine the hypothesis,” he says.
Moncrieff says the review was dependent on the studies that had already been done, none of which highlighted any difference between people who were experiencing symptoms of depression or had a history of it.
“It must be recognised that 5-HT is likely only one contributor to depression,” says Paul Albert at the University of Ottawa in Canada. “Given the large placebo effect in treatment of depression, it is likely that the contribution of other systems, including dopamine that is implicated in placebo effect, may be greater than that of 5-HT.”
“Antidepressants are an effective, NICE-recommended treatment for depression that can also be prescribed for a range of physical and mental health conditions,” a spokesperson for the Royal College of Psychiatrists told the Science Media Centre in the UK, referring to treatment guidelines from the National Institute for Health and Care Excellence (NICE) in England. “Antidepressants will vary in effectiveness for different people, and the reasons for this are complex. We would not recommend for anyone to stop taking their antidepressants based on this review, and encourage anyone with concerns about their medication to contact their [family doctor].”
The “serotonin hypothesis” of clinical depression is almost 50 years old. At its simplest, the hypothesis proposes that diminished activity of serotonin pathways plays a causal role in the pathophysiology of depression. This notion was based on the depressogenic effects of amine depleting agents such as reserpine, as well as the actions of antidepressant drugs such as monoamine oxidase inhibitors and tricyclic antidepressants, discovered by clinical serendipity, but later found in animal experimental studies to potentiate the effects of serotonin and other monoamines at the synapse (1).
This pattern of theory making – moving from the pharmacological actions of drugs with some efficacy in treatment to biochemical notions of causation – has been common in biological psychiatry. In such an undeveloped field this approach, though logically precarious, has been a useful heuristic and, in the case of the dopamine hypothesis of psychosis, has been strikingly upheld by advanced brain imaging techniques (2). However, the serotonin hypothesis of depression has not been clearly substantiated. Indeed, dogged by unreliable clinical biochemical findings and the difficulty of relating changes in serotonin activity to mood state, the serotonin hypothesis eventually achieved “conspiracy theory” status, whose avowed purpose was to enable industry to market selective serotonin reuptake inhibitors (SSRIs) to a gullible public (3).
IS SEROTONIN STILL RELEVANT TO AN UNDERSTANDING OF DEPRESSION?
In biological psychiatry, pathophysiological hypotheses are not easily refuted. More often they simply seem to become irrelevant as new models of causation take their place. In an era of neural networks and systems level neuroscience, “single” neurotransmitter theories of depression look increasingly implausible. Is serotonin still worth thinking about in relation to depression?
The best evidence that serotonin plays a role in the pathophysiology of depression comes from studies of “tryptophan depletion”, where an acute dietary manipulation is employed to produce a transient lowering in brain serotonin activity through diminishing availability of its precursor amino acid, tryptophan. In healthy participants with no risk factors for depression, tryptophan depletion does not produce clinically significant changes in mood; however, recovered depressed patients free of medication can show brief, clinically relevant, depressive symptomatology (4). Interestingly, the same is true of recovered depressed patients undergoing catecholamine depletion with alpha-methyl-para-tyrosine (5).
Overall, this evidence suggests that impairing serotonin function can cause clinical depression in some circumstances, but is neither necessary nor sufficient. In addition, the depressogenic effects of tryptophan depletion are much more apparent in people who have experienced prior episodes of depression than in those simply at high risk of illness, for example by virtue of a strong family history (6). This suggests that low serotonin function may compromise mechanisms involved in maintaining recovery from depression rather than having a primary effect to lower mood in all vulnerable people.
These findings also hint at a role for diminished tryptophan availability in triggering depression, particularly in people with a previous history of illness. Interestingly, lower plasma levels of tryptophan are one of the few reasonably robust findings in patients with more severe forms of depression (7) and, more recently, have been linked to peripheral inflammation and consequent induction of the tryptophan metabolizing enzyme indoleamine 2,3-dioxygenase (8). Inflammation could therefore produce depression in vulnerable individuals by lowering plasma tryptophan and diminishing brain serotonin activity. Conceivably, such an effect could explain the diminished efficacy of SSRIs in depressed patients with high levels of inflammatory biomarkers
CONCLUSIONS
Simple biochemical theories that link low levels of serotonin with depressed mood are no longer tenable. However, experimental and computational accounts of how serotonin influences emotional processing throw an intriguing light on the neuropsychology of depression and its pharmacological treatment.
Whether this information can be harnessed to predict therapeutic response to SSRI treatment at an individual level is an important topic for clinical translation.
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